Current molecular pharmacology最新文献

{"title":"The Therapeutic Potential of Targeting the Connexin43 as a New Approach to Reducing Post-surgical Adhesion","authors":"Alireza Moslem, Rozita Khodashahi, Gordon A Ferns, Mohsen Aliakbarian, Mohammad-Hassan Arjmand","doi":"10.2174/0118761429302171240621101944","DOIUrl":"10.2174/0118761429302171240621101944","url":null,"abstract":"<p><p>Post-surgical peritoneal adhesions are a serious problem causing complications, such as bowel obstruction, infertility, and pain. There are currently no effective ways of preventing post-surgical adhesions. Excess secretion of proinflammatory cytokines and profibrotic molecules by immune cells and adherent fibroblasts are the main mechanism that promotes post-operative fibrotic scars. Although many studies have been conducted on the pathological causes of this disorder, there are still many unknown facts in this matter, so assessment of the role of different molecules in causing inflammation and adhesion can lead to the creation of new treatment methods. Connexins are a group of proteins related to gap junctions that have a role in cell communication and transmitted signaling between adjacent cells. Between different types of connexin protein isoforms, connexin43 is known to be involved in pathological conditions related to inflammation and fibrosis. Recent studies have reported that inhibition of connexin43 has the potential to reduce inflammation and fibrosis by reducing the expression of molecules like α-SMA and plasminogen activator inhibitor (PAI) that are involved in the early stages of adhesion formation. As well as, inhibition of connexin43 may have therapeutic potential as a target to prevent post-surgical peritoneal adhesions.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429302171"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repair Effect of siRNA Double Silencing of the Novel Mechanically Sensitive Ion Channels Piezo1 and TRPV4 on an Osteoarthritis Rat Model.","authors":"Zhuqing Jia, Jibin Wang, Xiaofei Li, Qining Yang, Jianguo Han","doi":"10.2174/0118761429317745241017114020","DOIUrl":"10.2174/0118761429317745241017114020","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to explore the repair effect of siRNA-mediated double silencing of the mechanically sensitive ion channels Piezo1 and TRPV4 proteins on a rat model of osteoarthritis.</p><p><strong>Methods: </strong>Piezo1 and TRPV4 interference plasmids were constructed using siRNA technology. Sprague Dawley (SD) rats were divided into four groups: the model group, siRNA-Piezo1, siRNA-TRPV4, and double gene silencing groups. Improved Mankin and OARSI scores were calculated based on H&E staining and Safranin O-fast green staining. Immunohistochemical staining was used to determine expression levels of aggrecan and Collagen II proteins. Piezo1, TRPV4, Aggrecan, and Collagen II mRNA expression in knee joint cartilage tissue were assessed using qRT-PCR.</p><p><strong>Results: </strong>Lentivirus-mediated siRNA plasmids (siRNA-Piezo1, siRNA-TRPV4, and double-gene siRNA silencing plasmids) achieved > 90% transfection efficiency in chondrocytes. RT-PCR results indicated that double-gene siRNA silencing plasmids silenced Piezo1 and TRPV4 mRNA expression (P < 0.05). Modified Mankin and OARSI scores revealed that the repair effect in the double gene silencing group was significantly better than that of the siRNA-Piezo1 and siRNA-TRPV4 groups (P < 0.05). Relative expression of aggrecan and collagen II mRNA in the double gene-silenced group was significantly higher than in the siRNA-Piezo1 and siRNA-TRPV4 groups (P < 0.05).</p><p><strong>Conclusion: </strong>Double silencing Piezo1 and TRPV4 plays a key role in cartilage repair in an osteoarthritic rat model by promoting the expression of Aggrecan and Collagen II.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":"17 1","pages":"e18761429317745"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydromyricetin Improves Myocardial Functioning by Influencing Autophagy Through SNHG17/Mir-34a/SIDT2 Axis.","authors":"Hai Xiao, Yan Xiao, Xueliang Zeng, Huihui Xie, Ziyao Wang, Yu Guo","doi":"10.2174/0118761429374180250212114144","DOIUrl":"10.2174/0118761429374180250212114144","url":null,"abstract":"<p><strong>Background: </strong>Diabetic cardiomyopathy (DCM) is a common and severe complication of Diabetes Mellitus (DM). Dihydromyricetin (DHM) is a flavonoid compound with potential cardioprotective effects, but the mechanism of DHM in diabetes-induced myocardial damage and autophagy is not fully understood.</p><p><strong>Objective: </strong>The objective of this study is to evaluate the effects of DHM on cardiac function and pathological features of DCM, with a particular focus on its impact on the SNHG17/miR-34a/SIDT2 pathway.</p><p><strong>Methods: </strong>In vivo experiments: After constructing the DM mice model, it was treated with different doses of DHM. Masson's staining and collagen deposition/fibrosis markers were used to evaluate the effect of DHM on cardiac fibrosis in DM mice. In vitro experiments: 3-[4,5- dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were used to determine the influence of DHM on cell viability and apoptosis, respectively, in high glucose-induced HL-1 cells. Enzyme-labeled Immunosorbent Assay was used to detect levels of cardiac enzyme and inflammation-related factors, while Western blot analyzed the levels of AMPK/mTOR and autophagy-related proteins.</p><p><strong>Results: </strong>DHM significantly improved cardiac function in DM and reduced Renin-angiotensin-aldosterone system markers, alongside decreasing markers of cardiomyocyte damage. DHM mitigated myocardial fibrosis, inflammatory marker levels, and autophagy dysregulation while upregulating lncRNA SNHG17 expression. Mechanistically, DHM acted through the SNHG17/miR-34a/SID1 transmembrane family member 2 (SIDT2) axis, reducing miR-34a expression and restoring SIDT2-mediated autophagy balance, ultimately alleviating apoptosis, inflammation, and fibrosis in diabetic cardiac tissue and high-glucose-induced HL-1 cells.</p><p><strong>Conclusion: </strong>DHM improves cardiac function and mitigates DCM progression by targeting the SNHG17/miR-34a/SIDT2 regulatory axis, thereby reducing inflammation, fibrosis, and autophagy dysregulation. These findings provide mechanistic insights into DHM’s cardioprotective effects, supporting its potential as a therapeutic agent for DCM.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429374180"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143461269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory Mechanisms of STAT3 in GBM and its Impact on TMZ Resistance","authors":"Guangyao Lv, Xueying Li, Hongtu Deng, Jianqiao Zhang, Xinfu Gao","doi":"10.2174/0118761429386400250415053351","DOIUrl":"10.2174/0118761429386400250415053351","url":null,"abstract":"<p><p>STAT3, a key member of the Signal Transducer and Activator of Transcription (STAT) family, plays a vital role in the development and progression of glioblastoma (GBM), as well as in the resistance to the chemotherapy drug temozolomide (TMZ). This review outlines the dysregulation of STAT3 in GBM, focusing on its activation mechanisms and its contribution to TMZ resistance. STAT3 can be activated by cytokines, like IL-6, growth factors, and membrane receptors, like EGFR. In GBM, constitutively active STAT3 enhances tumor growth and therapy resistance. Specifically, resistance to TMZ, a standard chemotherapeutic agent for GBM, is facilitated by STAT3-induced expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase and anti-apoptotic proteins like Bcl-2, as well as through the regulation of microRNAs. To combat TMZ resistance in GBM, strategies that inhibit STAT3 activity have been explored. Recent advancements, such as the use of small molecule inhibitors targeting STAT3 and its upstream or downstream regulators, RNA-based therapies, as well as the development of nanocarriers for targeted delivery of STAT3-<i>targeting small interfering RNA</i> across the blood-brain barrier, have demonstrated significant potential in enhancing the sensitivity of GBM to TMZ. These targeted therapies hold promise for improving the treatment outcomes of patients with GBM.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429386400"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144052214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ergothioneine Suppresses Amyloid β-Induced Tau Phosphorylation and Cytotoxicity by Inactivating Glycogen Synthase Kinase-3β in Cultured Neurons","authors":"Fumiya Shibagaki, Yusei Hayashi, Satoshi Matsumoto, Noritaka Nakamichi","doi":"10.2174/0118761429387340250507055903","DOIUrl":"10.2174/0118761429387340250507055903","url":null,"abstract":"<p><strong>Background: </strong>Amyloid-beta (Aβ) oligomers, formed by Aβ aggregation, are the causative agent of Alzheimer's disease and induce the hyperphosphorylation of tau protein (Tau) and neurotoxicity. The antioxidant ergothioneine (ERGO) is transferred to the brain after oral ingestion and protects against Aβ- induced neurotoxicity and cognitive dysfunction. However, the impact of ERGO on Aβ oligomer-induced Tau phosphorylation remains unclear.</p><p><strong>Objective: </strong>To investigate the effects of ERGO on Aβ-induced Tau phosphorylation and their mechanism in neurons.</p><p><strong>Method: </strong>SH-SY5Y cells differentiated into cholinergic neuron-like cells or primary cultured neurons derived from the murine hippocampus were pretreated with ERGO and exposed to Aβ_25-35 oligomers. Cytotoxicity was evaluated by assessing the chemiluminescence of dead cell-derived proteases. The expression of phosphorylated (p-) Tau at serine 396, p-glycogen synthase kinase-3 beta (GSK-3β) at serine 9, amyloid precursor protein (APP), beta-site amyloid precursor protein cleaving enzyme 1 (BACE1; β-secretase), and nicastrin, which is a component protein of the γ-secretase complex, was assessed by western blotting.</p><p><strong>Result: </strong>Differentiated SH-SY5Y cells exhibited increased neurite outgrowth and mRNA expression of <i>choline acetyltransferase</i>, and showed cholinergic neuron-like characteristics compared with those of undifferentiated cells. ERGO significantly suppressed the Aβ_25-35 oligomer-induced increased cytotoxicity and p-Tau expression in differentiated SH-SY5Y cells and cultured hippocampal neurons. ERGO recovered the decreased expression of p-GSK-3β at serine 9, indicating its inactivation, and the increased expression of APP, BACE1, and nicastrin induced by Aβ_25-35 oligomer exposure in cultured hippocampal neurons. These ERGO effects on Aβ_25-35 oligomers were inhibited by treatment with LY294002, which activated GSK-3β.</p><p><strong>Conclusion: </strong>ERGO may suppress the increased expression of p-Tau and proteins involved in Aβ production induced by Aβ oligomers by inactivating GSK-3β, thereby mitigating neurotoxicity.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429387340"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RBM3 Inhibits the Cell Cycle of Cutaneous Squamous Cell Carcinoma through the PI3K/AKT Signaling Pathway.","authors":"Yan Huang, Weichao Sun, Danli Zhu, Li Liu, Jianguo Feng, Qian Yi","doi":"10.2174/0118761429323760240712050006","DOIUrl":"10.2174/0118761429323760240712050006","url":null,"abstract":"<p><strong>Background: </strong>RBM3 is a key RNA-binding protein that has been implicated in various cellular processes, including cell proliferation and cell cycle regulation. However, its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood.</p><p><strong>Aims: </strong>We aimed to investigate the expression levels of RNA-binding motif protein 3 (RBM3) in patients with cSCC and evaluate its effect on cell ability in cSCC and its underlying regulatory mechanisms.</p><p><strong>Methods: </strong>The expression of RBM3 in cSCC tissues and A431 cells was determined via immunohistochemistry and western blotting. Plenti-CMV-RBM3- Puro was used to overexpress RBM3. The effect of RBM3 on the proliferation ability of cSCC cells was evaluated using MTT and colony formation assay. Cell apoptosis and cell cycle were determined using flow cytometry, while the protein expressions of BAX, NF-κB, BCL2, CASPASE 3, CYCLIN B, CYCLIN E, CDK1, phosphorylated (P)-CDK1, CDK2, P-CDK2, ERK, P-ERK, P-AMPK, AKT, P-AKT, MDM2, and P53 were assessed using western blotting.</p><p><strong>Results: </strong>RBM3 expression was significantly downregulated in cSCC tissues and A431 cells. RBM3 overexpression significantly inhibited the cell proliferation and colony formation ability of A431. Notably, RNA-seq results showed that the differentially expressed genes associated with RBM3 were primarily involved in the regulation of the cell cycle, oocyte meiosis, and P53 signaling pathway, as well as the modulation of the MAPK, AMPK, Hippo, mTOR, PI3K/AKT, Wnt, FoxO, and NF-κB signaling pathways. Additionally, our findings demonstrated that overexpression of RBM3 inhibited cell proliferation and induced cell cycle arrest of cSCC through modulation of the PI3K/AKT signaling pathway.</p><p><strong>Conclusion: </strong>This study provides novel insights into the suppressive roles of RBM3 in cell proliferation and the cell cycle in cSCC and highlights its therapeutic potential for cSCC.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429323760"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective Potential of Tanshinone-IIA in Mitigating Propionic Acidinduced Experimental Autism-like Behavioral and Neurochemical Alterations: Insights into c-JNK and p38MAPK Pathways","authors":"Kajal Sherawat, Sidharth Mehan, Zuber Khan, Aarti Tiwari, Ghanshyam Das Gupta, Acharan S Narula","doi":"10.2174/0118761429326799241121104310","DOIUrl":"10.2174/0118761429326799241121104310","url":null,"abstract":"<p><strong>Introduction: </strong>Autism is a neurodevelopmental disorder associated with mitochondrial dysfunction, apoptosis, and neuroinflammation. These factors can lead to the overactivation of c-JNK and p38MAPK.</p><p><strong>Methods: </strong>In rats, stereotactic intracerebroventricular (ICV) injection of propionic acid (PPA) results in autistic-like characteristics such as poor social interaction, repetitive behaviours, and restricted communication. Research has demonstrated the beneficial effects of phytochemicals derived from plants in treating neurological disorders. Tanshinone-IIA (Tan-IIA) is a chemical found in the root of Salvia miltiorrhiza. It has neuroprotective potential by inhibiting c-JNK and p38MAPK against behavioral and neurochemical alterations in PPA-induced autistic rats. We observe behavioral changes, alterations in apoptotic markers, myelin basic protein (MBP), neurofilament-Light (NEFL), inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and neurotransmitter imbalances using different brain regions (cerebral cortex, hippocampus, striatum), as well as biological samples, cerebrospinal fluid (CSF), and blood plasma.</p><p><strong>Results: </strong>Persistent administration of 30 mg/kg and 60 mg/kg Tan-IIA via intraperitoneal injection reduced these alterations dose-dependently. Anisomycin (3 mg/kg.,i.p.) as a SAPK (c-JNK and p38MAPK) agonist was administered to assess the neuroprotective effect of Tan-IIA in autistic rats. Tan- IIA's molecular interactions with c-JNK and p38MAPK were confirmed using silico analysis. We also observed gross morphological, histopathological, and Luxol Fast Blue (LFB) myelin straining changes in whole and coronal brain sections.</p><p><strong>Conclusion: </strong>Thus, Tan-IIA has a neuroprotective potential by inhibiting the c-JNK and p38MAPK signalling pathways, which reduces the behavioral and neurochemical abnormalities induced by PPA in adult Wistar rats, indicating that current results should be studied further for the diagnosis and treatment of autism.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429326799"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142741579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chrysin: A Potential Antiandrogen Ligand to Mutated Androgen Receptors in Prostate Cancer.","authors":"Ahtziri Socorro Carranza-Aranda, Anne Santerre, Aldo Segura-Cabrera, Albertina Cárdenas-Vargas, Moisés Martínez-Velázquez, Rodolfo Hernández-Gutiérrez, Sara Elisa Herrera-Rodríguez","doi":"10.2174/0118761429350210250102131611","DOIUrl":"10.2174/0118761429350210250102131611","url":null,"abstract":"<p><strong>Background: </strong>Androgen receptor mutations, particularly T877A and W741L, promote prostate cancer (PCa). The main therapies against PCa use androgen receptor (AR) antagonists, including Bicalutamide; but these drugs lose their effectiveness over time. Chrysin is a flavonoid with several biological activities, including antitumoral properties; however, its potential as an antiandrogen must be explored.</p><p><strong>Objective: </strong>The present study aimed to characterize and compare the molecular interactions of chrysin with wild-type and mutated ARs and their cytotoxic effect in an in vitro model of PCa.</p><p><strong>Methods: </strong>The affinities and molecular interactions of Bicalutamide and chrysin for the wild-type and mutated forms of AR were assessed by molecular docking. The MTT assay was used to evaluate the cytotoxic effect of these ligands on the DU-145 (T877A) and PC3 (W741L) PCa cell lines and on non-tumoral RWPE-1 cells.</p><p><strong>Results: </strong>The molecular dockings predicted a higher affinity of chrysin for the mutated AR than the wild-type AR (WT-AR); meanwhile, Bicalutamide presented a higher affinity for WT-AR. The amino acid residues involved in molecular interactions within the binding site of these receptors changed according to the ligands and AR variants, affecting their affinity scores and biological effects (agonist/antagonists). Chrysin exerted a specific cytotoxic effect against the PCa tumoral cells but none against the non-tumoral cells. In contrast, Bicalutamide showed potent cytotoxicity against all cell lines.</p><p><strong>Conclusion: </strong>This study evidences the potential antiandrogen effect of chrysin on mutated AR and specific cytotoxicity against PCa cells, suggesting that this flavonoid could be considered for PCa therapy.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429350210"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term Uridine Treatment Alleviates Endoplasmic Reticulum Stress via Regulating Inflammation and Oxidative Stress in Lithium-Pilocarpine Model of Status Epilepticus","authors":"Birnur Aydin, Cansu Koc, Mehmet Cansev, Tülin Alkan","doi":"10.2174/0118761429315851240909104349","DOIUrl":"10.2174/0118761429315851240909104349","url":null,"abstract":"<p><strong>Background: </strong>Status Epilepticus (SE) leads to the development of epilepsy with the contribution of Endoplasmic Reticulum (ER) stress. Uridine, a pyrimidine nucleoside, has been shown to have neuroprotective and antiepileptogenic effects in animal models. This study aimed to determine whether uridine ameliorates ER stress and apoptosis following epileptogenic insult. Secondly, this study aimed to establish the effect of uridine on inflammatory and oxidative stress parameters that contribute to ER stress.</p><p><strong>Methods: </strong>Status epilepticus was induced using lithium-pilocarpine in adult male Sprague-Dawley rats. Following SE termination, rats were treated with uridine, 4-phenylbutyric acid (4-PBA), or saline twice daily for 48 h. Expressions of hippocampal glucose-regulated protein 78 (GRP78), Inositol- Requiring Protein 1 (IRE1α), Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK), and C/EBP Homologous Protein (CHOP) were determined by western blotting 48 h after SE. Uridine's effects on apoptosis, inflammation or oxidation were evaluated by analyses of cleaved caspase-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein expressions or pro-inflammatory cytokine levels or levels of oxidative stress markers, respectively.</p><p><strong>Results: </strong>Expressions of all ER stress-related proteins significantly increased 48 h after SE. Uridine treatment markedly decreased GRP78, IRE1α, and CHOP levels. A decrease in the PERK level was observed following the administration of 4-PBA; however, uridine had no effect. Cleaved caspase-3 and PARP1 levels were increased in the SHAM group, while uridine and 4-PBA treatment effectively decreased their expressions. Treatment with uridine significantly reduced Myeloperoxidase (MPO) and Malondialdehyde (MDA) levels while tending to increase Catalase (CAT) and Glutathione Peroxidase (GPx) levels. Uridine treatment also significantly attenuated levels of TNF-α and IL-1β, the pro-inflammatory cytokines, which increased 48 h post-SE.</p><p><strong>Conclusion: </strong>Our data indicate that uridine alleviates ER stress after SE. This effect may be attributed to the regulation of inflammation and oxidative stress. Uridine shows promise as a potential preventive agent for epilepsy.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":" ","pages":"e18761429315851"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142304519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct Thrombin Inhibitors Suppress Type 1 Diabetes Development through PI3K/p-AKT Pathway.","authors":"Ahmed G Alharbi, Hussien M Ali, Ahmed H Alhowail, Maha A Aldubayan, Mohamed S Abdel-Bakky","doi":"10.2174/0118761429374852250305153445","DOIUrl":"https://doi.org/10.2174/0118761429374852250305153445","url":null,"abstract":"<p><strong>Background: </strong>Diabetes mellitus type-1 is an immunological disease associated with low insulin release and hyperglycemia due to beta cell loss. No clear studies show the relationship between the coagulation cascade activation and diabetes mellitus type-1 development.</p><p><strong>Objective: </strong>The present work aimed to clarify the function of the active coagulation system in the progression of diabetes mellitus type-1 (T1DM). Furthermore, the possible protective action of direct thrombin inhibitors (dabigatran) against T1DM caused by streptozotocin (STZ)-induced T1DM in mice model was examined.</p><p><strong>Materials and methods: </strong>Forty Balb/c male albino mice were distributed into four different groups, with 10 mice in each group: normal, dabigatran (DAB)-treated, STZtreated, and STZ+DAB. Blood glucose, blood platelets, serum insulin, nuclear consistency, and pancreas histopathological changes were evaluated. Moreover, the expressions of PI3K, p-Akt, insulin, and fibrinogen were investigated in the pancreatic tissues via immunofluorescent technique.</p><p><strong>Results: </strong>The findings displayed enhanced islet expression of fibrinogen, p-Akt, and PI3K proteins along with thrombocytopenia in STZ-injected mice when equated to control. Furthermore, treatment with STZ reduced pancreatic insulin expression. DAB and STZ-cotreatment significantly diminished pancreatic tissue expression of fibrinogen, PI3K, and p-AKT, as well as increased platelet counts and pancreatic insulin expression.</p><p><strong>Conclusion: </strong>The evidence supported the activation of coagulation cascade in T1DM through the PI3K/AKT pathway. Using direct antithrombin therapy may open new avenues for T1DM prevention in high-risk diabetes individuals.</p>","PeriodicalId":93964,"journal":{"name":"Current molecular pharmacology","volume":"17 ","pages":"e18761429374852"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}